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1 From the School of Population Health, University of Queensland, Brisbane, Australia (TC and AD); the Epidemiology Services Unit, Health Information Branch, Queensland Health, Brisbane, Australia (TC, TII, and CM); the Viertel Center for Research in Cancer Control, Queensland Cancer Fund, Brisbane, Australia (PDB); Oxfam, Oxford (SD) Tropical Public Health Unit, Queensland Health, Cairns, Australia (DL); and the International Diabetes Institute, Melbourne, Australia (JS)
2 Supported by the Australian Department of Health and Ageing, state and territory governments, and pharmaceutical companies: Eli Lilly (Aust) Pty Ltd, Janssen - Cilag (Aust) Pty Ltd, Knoll Australia Pty Ltd, Merck Lipha s.a. Alphapharm Pty Ltd, Merck Sharp & Dohme (Aust), Pharmacia and Upjohn Pty Ltd, Roche Diagnostics, Servier Laboratories (Aust) Pty Ltd, SmithKline Beecham International, BioRad Laboratories Pty Ltd and HITECH Pathology Pty Ltd; Qantas Airways Ltd and the Australian Kidney Foundation. The Queensland phase of the study was partially funded by Queensland Health. 3 Reprints not available. Address correspondence to T Coyne, School of Population Health, The University of Queensland, Public Health Building, Herston 4029, Queensland, Australia. E-mail: t.coyne{at}sph.uq.edu.au.
ABSTRACT
Background: Epidemiologic evidence suggests that serum carotenoids are potent antioxidants and may play a protective role in the development of chronic diseases including cancers, cardiovascular disease, and inflammatory diseases. The role of these antioxidants in the pathogenesis of diabetes mellitus remains unclear.
Objective: This study examined data from a cross-sectional survey to investigate the association between serum carotenoids and type 2 diabetes.
Design: Study participants were adults aged 25 y (n = 1597) from 6 randomly selected cities and towns in Queensland, Australia. Study examinations conducted between October and December 2000 included fasting plasma glucose, an oral-glucose-tolerance test, and measurement of the serum concentrations of 5 carotenoid compounds.
Results: Mean 2-h postload plasma glucose and fasting insulin concentrations decreased significantly with increasing quintiles of the 5 serum carotenoids—-carotene, ß-carotene, ß-cryptoxanthin, lutein/zeaxanthin, and lycopene. Geometric mean concentrations for all serum carotenoids decreased (all decreases were significant except that of lycopene) with declining glucose tolerance status. ß-Carotene had the greatest decrease, to geometric means of 0.59, 0.50, and 0.42 µmol/L in persons with normal glucose tolerance, impaired glucose metabolism, and type 2 diabetes, respectively (P < 0.01 for linear trend), after control for potential confounders.
Conclusions: Serum carotenoids are inversely associated with type 2 diabetes and impaired glucose metabolism. Randomized trials of diets high in carotenoid-rich vegetables and fruit are needed to confirm these results and those from other observational studies. Such evidence would have very important implications for the prevention of diabetes.
Key Words: Type 2 diabetes • diabetes mellitus • impaired glucose tolerance • serum carotenoids • -carotene • ß-carotene • ß-cryptoxanthin • lutein/zeaxanthin • lycopene • antioxidant vitamins • diet • cross-sectional surveys • health surveys • nutrition
INTRODUCTION
Carotenoids are a wide range of compounds derived solely from plants; the major ones found in serum are -carotene, ß-carotene, ß-cryptoxanthin, lutein/zeaxanthin, and lycopene. Considerable epidemiologic evidence exists that some carotenoids are potent antioxidants and may play a protective role against the development of chronic diseases such as atherosclerosis (1, 2), stroke (3), certain cancers (4), and inflammatory diseases (5). Although obesity and physical inactivity are known to be major risk factors for type 2 diabetes, evidence suggests that oxidative stress also may contribute to the pathophysiology of type 2 diabetes (6). Multiple factors have been associated with increased oxidative stress in diabetes mellitus. These factors include glucose autoxidation that results in the production of free radicals, an increase in protein glycation (glucooxidation), and a decrease in antioxidant defenses. Enhanced oxidative stress is considered an underlying condition that is responsible for some of the complications of diabetes (7).
Serum or dietary vitamin A, E, and C concentrations have been hypothesized to be lower in persons with impaired glucose tolerance (IGT) or with type 2 diabetes than in those who have normal glucose tolerance (8, 9); nevertheless, there is conflicting evidence concerning these relations (10, 11). Several cross-sectional epidemiologic studies have reported an inverse relation between serum carotenoids and diabetes status (12–15), and yet intervention studies providing supplements of antioxidant vitamins have shown conflicting results (7, 16). In this study, we investigated the relations between the major serum carotenoids—-carotene, ß-carotene, ß-cryptoxanthin, lutein/zeaxanthin, and lycopene—and type 2 diabetes status in a cross-sectional population-based study in Queensland, Australia.
SUBJECTS AND METHODS
Subjects
The study was conducted between October and December 2000 as part of a national study, the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), to determine the prevalence of diabetes and associated cardiovascular disease risk factors among adults aged 25 y (17). Six urban sites (cities and towns) were randomly selected from census collector districts (CDs) in Queensland. The CDs were selected and with probability proportional to size. Noninstitutionalized adults aged 25 y who were residing in private dwellings were included in the survey if they had resided full-time at the address for 6 mo before the survey. Persons with physical or intellectual disabilities that precluded participation in the study were not included.
Trained interviewers conducted house-to-house interviews, and eligible participants were invited to attend a biomedical examination that included collection of blood samples, blood pressure measurements, and anthropometric measurements and the administration of standardized questionnaires related to diet as well as sociodemographic, lifestyle, and health-related characteristics. Details of the sampling framework and overall study design have been published elsewhere (18). A total of 1634 persons in Queensland completed the physical examination. Although the overall response rate in the study was low (50% of those invited and 30% of those estimated to be eligible), the internal validity and quality control of the data collection were high (18).
All respondents gave written informed consent to participate in the survey on arrival at the testing site.The study was approved by the International Diabetes Institute and The University of Queensland ethics committees.
Methods
Study participants arrived for the examination after having fasted for 12 h. Blood pressure measurements were taken by using a Dinamap sphygmomanometer (Critikon, Tampa, FL). Blood was drawn for fasting glucose and insulin determinations. Participants not taking hypoglycemic medication completed a 2-h oral-glucose-tolerance test (OGTT) after consuming a 75-g glucose drink. Fasting and 2-h glucose were measured enzymatically (glucose oxidase) on an Olympus AU600 analyzer (Olympus Optical Co, Tokyo, Japan). Insulin analysis was conducted for all participants aged >35 (n = 1303) by using the Human Insulin Specific RIA Kit (catalog #HI-14K; Linco Research Inc, St Charles, MO).
The lipids total and HDL cholesterol and triacylglycerol were measured enzymatically on an Olympus AU 600. LDL cholesterol was calculated from the equation of Friedewald et al (19):
RESULTS
The prevalence of diabetes and IGM according to demographic and health-related characteristics is shown in Table 2. There was no significant difference in diabetes status between males and females. Significant differences in diabetes status were evident for subjects by age, BMI, physical activity status, total and HDL cholesterol, triacylglycerol, and systolic blood pressure.
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TABLE 2. The prevalence of type 2 diabetes and impaired glucose metabolism by demographic and health-related characteristics for adults aged 25 y in the 2000 Queensland AusDiab study1
The relations between the 5 serum carotenoids and the various sociodemographic, anthropometric, and health-related variables are shown in Table 3. Although there were significant differences in mean serum carotenoids within many of these categories, age group, BMI, alcohol intake, and HDL and LDL cholesterol had significant relations with all the serum carotenoids. Apart from educational status, all the other variables in Table 3 were related to some but not all carotenoids.
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TABLE 3. Geometric mean (and 95% CI) concentrations of serum carotenoids by selected variables for adults aged 25 y in the 2000 Queensland AusDiab study1
The mean fasting plasma glucose, 2-h postload glucose, and fasting insulin by quintiles of each serum carotenoid are shown in Table 4. The median of each of the carotenoids is provided for each quintile. Mean 2-h postload glucose and fasting insulin concentrations decreased significantly with increasing quintiles of each serum carotenoid (P for trend < 0.05). Fasting glucose concentrations also decreased significantly with increasing quintiles of -carotene and ß-carotene (P < 0.01).
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TABLE 4. Age-adjusted mean fasting plasma glucose, 2-h postload plasma glucose, and fasting insulin by quintile (Q) of serum carotenoids for adults in the 2000 Queensland AusDiab study1
After adjustment for the potential confounders age; sex; BMI; physical activity; educational status; smoking; alcohol intake; vitamin use; total, HDL, and LDL cholesterol; triacylglycerol; and systolic and diastolic blood pressures, significant linear trends in serum carotenoid concentrations (except lycopene) by diabetes status were evident (Table 5). ß-Carotene showed the most decline; its geometric means were 0.59, 0.50, and 0.42 µmol/L in persons with normal glucose tolerance, IGM, and type 2 diabetes, respectively (P < 0.01 for linear trend).
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TABLE 5. Adjusted geometric mean (and 95% CI) concentrations of serum carotenoids by diabetes status for adults aged 25 y who participated in the 2000 Queensland AusDiab study1
DISCUSSION
The data from the current population study suggest that serum carotenoids are associated with diabetes status. Our study showed an increasing trend in 2-h postload plasma glucose and fasting insulin concentrations with decreasing quintiles of all of the carotenoids tested. A decreasing trend in fasting plasma glucose concentrations was observed with increasing quintiles of -carotene and ß-carotene. In addition, serum carotenoid concentrations showed a linear decrease with the degree of glucose tolerance abnormality. This decrease was significant for all of the carotenoids except lycopene. These findings are consistent with data reported by Ford et al (12) from the third National Health and Nutrition Examination Survey (NHANES III; 12). In NHANES III, Ford et al reported a significant linear decrease in ß-carotene and lycopene in persons with IGT and in persons with newly diagnosed diabetes compared with persons with normal glucose concentrations, after adjustment for confounding factors similar to those in our study. The association between serum carotenoid concentrations and diabetes status observed in our study was also consistent with associations reported in studies from several other countries (13–15, 30, 31).
Because of the cross-sectional design of our study, however, it is not possible to draw inferences as to whether the lower serum carotenoid concentrations found in participants with diabetes are the result of increased utilization of these antioxidants due to the oxidative stress effects of the disease or whether the low concentrations are involved in the pathogenesis of the disease and reflect low intakes of carotenoid-rich vegetables and fruit. It has been postulated that the lower serum carotenoid concentrations found in this study may be due to the oxidative stress effects of IGM. Research has shown that oxidative stress, an imbalance in which the production of free radicals overwhelms the body's antioxidant defenses, is involved in the causation and progression of type 2 diabetes (32). There currently is considerable evidence that hyperglycemia, hyperinsulinemia, and insulin resistance result in greater reactive oxygen species production that contributes to oxidative stress in diabetes (33), and that this greater reactive oxygen species production may be beyond the capacity of the antioxidant defense mechanisms (34). Oxidative stress and free radical activity have been reported to be involved in the pathogenesis of type 1 diabetes (35), as well as in the development of complications associated with type 2 diabetes (36, 37). It is postulated that the oxidative stress associated with diabetes is responsible for the reduced carotenoid concentrations found in this study, which suggests that glucose intolerance is influencing the carotenoid concentrations, rather than the low carotenoid concentrations being causally related to diabetes status.
It has also been suggested that the oxidative stress observed in persons with glucose impairment is due to lower antioxidant concentrations. Facchini et al (38) suggested that insulin-mediated glucose disposal in healthy persons is significantly related to lipid hydroperoxide concentrations and fat-soluble antioxidant vitamins. Their work showed that nondiabetic subjects with insulin resistance had high plasma lipid peroxidation values well before the development of IGT or type 2 diabetes. They observed significant inverse associations between steady state plasma glucose values and -carotene, ß-carotene, lutein, -tocopherol, and -tocopherol in 36 healthy nondiabetic volunteers. Facchini et al also observed that the higher the steady state plasma glucose, the more insulin resistant the person. They hypothesized that insulin resistance can result in greater lipid peroxidation, which is accompanied by a decrease in plasma antioxidant concentrations. Conversely, lipid peroxidation is accelerated by low antioxidant activity, which could impair insulin action and result in diabetes (38). Thus it is possible that oxidative stress is a result of low antioxidant concentrations in persons who already have IGM and type 2 diabetes.
Several studies have shown a relation between vegetable or carotenoid intake and diabetes status (9, 14, 31). Suzuki et al (15) found a significantly lower odds ratio for high glycated hemoglobin (Hb A1c) among those with the highest intakes of carrots and pumpkin than among those with low intakes. The large EPIC-Norfolk study found that persons with higher intakes of vegetables and fruit have higher serum carotenoid concentrations and lower risk of type 2 diabetes than do those with lower intakes (39). Montonen et al (9) reported that, in older adults, ß-cryptoxanthin intake was inversely associated with reduced risk of type 2 diabetes. Ylönen et al (13) reported advantageous associations with both dietary and plasma carotenoids and glucose status among males but not among females in the Botnia Dietary Study.
Serum carotenoids are considered reliable markers of vegetable and fruit intake, and our study did find significant associations between the approximated vegetable and fruit intakes and serum concentrations of -carotene, ß-carotene, ß-cryptoxanthin, and lutein/zeaxanthin (40). We did not, however, find a significant association between glucose intolerance and self-reported vegetable and fruit intake or dietary ß-carotene intake (not shown). This lack of association may have been due to the crudeness of our methods for estimating vegetable and fruit intakes.
We recognize that residual confounding may have occurred in our study because of suboptimal measurements of several factors. For instance, concentrations of carotenoids (except lycopene) in our study were significantly lower among smokers, which is consistent with other studies (12). However, there may be residual confounding because of our simple categorization of smoking. This could have enhanced the magnitude of the association between serum carotenoids and glucose status, but it is not likely to explain most of the association.
Whereas our findings and data from other studies suggest a probable association between several carotenoids and diabetes, they do not establish a causal relation. In a clinical trial among US male health professionals, Liu et al (16) found no difference in the incidence of diabetes between the group receiving ß-carotene supplements and the control group. Liu et al concluded, however, that the results of their trial of ß-carotene supplementation "should not be interpreted as refuting the findings of observational studies that suggest that increased intake of vegetables rich in carotenoids and other antioxidants may decrease the risk of type 2 diabetes" (16).
Diabetes is increasing in most countries of the world today and will continue to increase (41). As populations continue to age and as overweight and obesity continue to escalate, especially among children, diabetes will become an increasing burden on the health system. Lifestyle interventions have shown a dramatic reduction in risk of diabetes among those with IGT (42, 43). However, strategies for both primary and secondary prevention will be necessary to reduce the burden of diabetes in future years and generations in both developed and developing countries. Clinical trials based on diets high in carotenoid-rich vegetables and fruit may provide important insight in relation not only to the prevention of complications of diabetes, but also to reducing the risk of developing the disease, especially among those with IGT.
ACKNOWLEDGMENTS
TC was responsible for the concept and conduct of the study and preparing the manuscript. TII performed the statistical analysis and writing the results section. PDB and AD provided technical assistance on the data analysis. JS, SD, and CM provided details regarding the study methods. DL gave technical assistance on writing and interpretation. None of the authors had a personal or financial conflict of interest.
REFERENCES